Therapeutics that use RNA interference (RNAi) as their mechanism of action have great promise for the treatment of human disease. For example, siRNA has attractive features for use as a therapeutic, including: (i) the ability to target essentially any gene (thus, all targets are in principle druggable), (ii) potent, single-digit, picomolar IC50's (concentration required for 50% inhibition) for mRNA inhibition in well-designed siRNAs, (iii) chemical modifications and sequence designs that can minimize off-target effects and immune stimulation without compromising potency and target specificity, and (iv) a catalytic RNAi mechanism of action, resulting in extended siRNA inhibition of mRNA target expression. Although a major obstacle to the translation of siRNA into an effective and efficient therapeutic is the delivery of the nucleic acid to the target, siRNA-based experimental therapeutics have reached the clinic.
Therapeutics investigated for cancer treatment are primarily administered systemically and use some type of synthetic compounds (positively charged lipids or polymers) in their formulations to deliver siRNA. A number of these formulations are now called nanoparticles (NPs). CALAA-01 was the first siRNA-based therapeutic to reach the clinic for the treatment of cancer. This targeted nanoparticle contains a cyclodextrin-based polycation (CDP) that assembles with siRNA via electrostatic interactions between positive charges on the polymer and negative charges on the siRNA backbone. CALAA-01 was able to deliver siRNA to solid tumors in patients and release functional siRNA that inhibited the target using an RNAi mechanism (the first example in a human). While CALAA-01 revealed several positive attributes, one of its shortcomings is that it has a very limited circulation time. The fast clearance of CALAA-01 that is observed in animals (mice, rats, dogs, and non-human primates) is also observed in humans.